Calcium in nerve cells plays an important role in transferring signals between the nerve cells. There are several channels for calcium. However, when a terminal stimulus is transferred thereto, a voltage-dependent calcium channel (voltage-dependent Ca2+ channel) works primarily. That is, the voltage-dependent calcium channel as a membrane protein regulates various intracellular functions such as muscle contraction, neurogenesis, synapse plasticity, secretion of neurotransmitter and hormone, gene expression, etc. by controlling an inflow of calcium ion from a cell exterior.
The voltage-dependent calcium channel can be functionally classified depending on its biophysical property: a low voltage-activated Ca2+ channel (hereinafter referred to as “LVA”), which is activated at lower voltage; and a high voltage-activated Ca2+ channel (hereinafter referred to as “HVA”), which is activated at higher voltage. The HVA calcium channel is subdivided into L-, P/Q-, N- and R-types depending on a pharmacological property of the current induced thereby. The LVA calcium channel is characterized by small conductivity being very quickly activated and inactivated. Thus, it is commonly called T (transient)-type calcium channel (Tsien, R. W. et al., Trends Neurosci. 1988, 11, 431-438).
It has been reported that the T-type calcium channel is involved in bursting firing of nerve cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), pacemaker activity of the heart (Zhou, Z et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of the hormone aldosterone (Rossier, M. F. et al., Endocrinology 1996, 137, 4817-4826), and fertilization (Arnoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009). In addition, the T-type calcium channel may become over-expressed due to genetic or environmental causes, leading to diseases such as epilepsy (Tsakiridou, E. et al., J. Neurosci. 1995, 15, 3110-3117), high blood pressure (Self, D. A. et al. J. Vacs. Res. 1994, 31, 359-366), ventricular hypertrophy (Nuss, H. B. et al., Circ. Res. 1995, 73, 777-7825), pain (Shin, H. S. et al., Science 2003, 302, 117-119), and angina pectoris (Van der Vring, J. A. et al., Am. J. Ther. 1999, 6, 229-233).
Recently, it has been also reported that the T-type calcium channel is involved in pain relief (Ikeda, H. et al., Science 2003, 299, 1237-1240). The HVA calcium channel is evenly expressed from the peripheral sensory cells to the central nervous system, and is well known to play an important role in transmission of the sense of pain and reflection. The inhibitors against these channels are already commercially available as various anodynes (Schaible, Prog. Brain Res., 2000, 129:173-190).
However, it is not yet clearly understood how the LVA calcium channel that generates the T-type calcium current can regulate pain. The reason why the T-type calcium current is categorized as one of the functions of the LVA calcium channel is that when the excitability of nerve cells lowers, the calcium current are generated so that the excitability increases again (Llinas, J. Physiol (Lond), 1981, 315:549-567; McCormick, Neuroscience, 1990, 39:103-113). Thus, the nerve cells excited by the T-type calcium channel have the property of burst firings and induce a type of excitability different from tonic firings (Llinas, J. Physiol (Lond), 1981, 315:549-567).
The channel protein of the T-type calcium channel is encoded by three different genes, which are referred to as alpha(α)1G, α1H and α1I, respectively (Perez-Reyes, Nature, 1998, 391:896-900). It is known that the α1G and α1H T-type calcium channels are expressed in the back of the spinal cord, and that the α1G is expressed in thalamocortical relay neurons (Talley, J. Neurosci., 1999, 19:1895-1911), and that is identical with the delivery path of the visceral pain. Recently, it has been proved in an experiment using a T-type calcium current inhibitor, mibefradil (registered trademark: Posicor, Hoffman La Roche Ltd.) that the function of the T-type calcium current in the peripheral nerves is related to hyperalgesic reaction against thermo-stimuli or mechanical stimuli by reducing agents (Todorovic, Neuron, 2001, 31:75-85), however, it has not yet been found which T-type calcium channel is related. Mibefradil was initially known for lowering blood pressure (Clozel, Cardiovasc Drugs Ther., 1990, 4:731-736; Hefti, Arzneimittelforschung, 1990, 40:417-421), and was reported to have a suppression effect on several calcium channels including T-type calcium channel (Viana, Cell Calcium, 1997, 22:299-311). Recently, it has been reported that Mibetradil has the most selective suppression effect on T-type calcium channels.
However, there were no effective T-type calcium channel blockers except for Mibefradil and ZD7288 (Felix, R. et al., Biochem. Biophys. Res. Commun. 2003, 311, 187-192). Accordingly, by developing a selective T-type calcium channel blocker, it may be possible to develop an epochal treating agent for cardiovascular diseases such as high blood pressure, angina pectoris, heart failure and arrhythmia, as well as pain-related diseases.